Systems and methods for reducing the likelihood of inducing collateral neural activity during neural stimulation threshold test procedures

ABSTRACT

Test procedures for determining a neural stimulation threshold of a patient. In one embodiment, the procedure includes applying a test stimulation signal to the patient and monitoring the patient for a response to the test stimulation signal. The procedure can further include determining a first neural stimulation threshold and calculating a second neural stimulation threshold. The first neural stimulation threshold corresponds to the lowest intensity test stimulation signal that evokes a patient response. The second neural stimulation threshold corresponds to a treatment stimulation signal directed toward affecting a neural activity within the patient.

CROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] This application is a Continuation-in-Part of U.S. patentapplication Ser. No. 09/978,134, entitled “Systems and Methods forAutomatically Optimizing Stimulus Parameters and ElectrodeConfigurations for Neuro-Stimulators,” filed Oct. 15, 2001, which isincorporated herein by reference.

TECHNICAL FIELD

[0002] The present disclosure is related to systems and methods forreducing the likelihood of inducing collateral neural activity whiledetermining threshold parameters for electrically stimulating a regionin the cortex or other area of the brain.

BACKGROUND

[0003] A wide variety of mental and physical processes are controlled orinfluenced by neural activity in particular regions of the brain. Theneural-functions in some areas of the brain (i.e., the sensory or motorcortices) are organized according to physical or cognitive functions.There are also several other areas of the brain that appear to havedistinct functions in most individuals. In the majority of people, forexample, the areas of the occipital lobes relate to vision, the regionsof the left interior frontal lobes relate to language, and the regionsof the cerebral cortex appear to be consistently involved with consciousawareness, memory, and intellect.

[0004] Many problems or abnormalities with body functions can be causedby damage, disease and/or disorders in the brain. Effectively treatingsuch abnormalities may be very difficult. For example, a stroke is avery common condition that damages the brain. Strokes are generallycaused by emboli (e.g., obstruction of a vessel), hemorrhages (e.g.,rupture of a vessel), or thrombi (e.g., clotting) in the vascular systemof a specific region of the brain, which in turn generally cause a lossor impairment of a neural function (e.g., neural functions related tofacial muscles, limbs, speech, etc.). Stroke patients are typicallytreated using various forms of physical therapy to rehabilitate the lossof function of a limb or another affected body part. Stroke patients mayalso be treated using physical therapy plus an adjunctive therapy suchas amphetamine treatment. For most patients, however, such treatmentsare minimally effective and little can be done to improve the functionof an affected body part beyond the recovery that occurs naturallywithout intervention.

[0005] Neural activity is governed by electrical impulses or “actionpotentials” generated in and propagated by neurons. While in a quiescentstate, a neuron is negatively polarized and exhibits a resting membranepotential that is typically between −70 and −60 mV. Through chemicalconnections known as synapses, any given neuron receives from otherneurons excitatory and inhibitory input signals or stimuli. A neuronintegrates the excitatory and inhibitory input signals it receives, andgenerates or fires a series of action potentials when the integrationexceeds a threshold potential. A neural firing threshold may be, forexample, approximately −55 mV. Action potentials propagate to theneuron's synapses, where they are conveyed to other neurons to which theneuron is synaptically connected.

[0006] The neural activity in the brain can be accordingly influenced byelectrical energy that is supplied from a man-made source such as awaveform generator. Various neural functions can thus be promoted ordisrupted by applying an electrical current to the cortex or otherregion of the brain. As a result, researchers have attempted to treatdamage, disease and disorders in the brain using electrical or magneticstimulation signals to control or affect brain functions. One treatmentapproach, transcranial electrical stimulation (TES), involves placing anelectrode on the exterior of the scalp and delivering an electricalcurrent to the brain through the scalp and skull. Another treatmentapproach, transcranial magnetic stimulation (TMS), involves producing ahigh-powered magnetic field adjacent to the exterior of the scalp overan area of the cortex. Yet another treatment approach involves directelectrical stimulation of neural tissue using implanted electrodes.

[0007] A neural stimulation signal may comprise a series or train ofelectrical or magnetic pulses that can affect neurons within a targetneural population, and may be defined or described in accordance withstimulation signal parameters including pulse amplitude, pulsefrequency, duty cycle, stimulation signal duration, and/or otherparameters. Electrical or magnetic stimulation signals applied to apopulation of neurons can depolarize neurons within the populationtoward their threshold potentials. Depending upon stimulation signalparameters, this depolarization can cause neurons to generate or fireaction potentials. Neural stimulation that elicits or induces actionpotentials in a functionally significant proportion of the neuralpopulation to which the stimulation is applied is referred to assupra-threshold stimulation; neural stimulation that fails to elicitaction potentials in a functionally significant proportion of the neuralpopulation is defined as sub-threshold stimulation. In general,supra-threshold stimulation of a neural population triggers or activatesone or more functions associated with the neural population, butsub-threshold stimulation by itself fails to trigger or activate suchfunctions. Supra-threshold neural stimulation can induce various typesof measurable or monitorable responses in a patient. For example,supra-threshold stimulation applied to a patient's motor cortex caninduce muscle fiber contractions.

[0008] Although electrical or magnetic stimulation of neural tissue maybe directed toward producing an intended type of therapeutic,rehabilitative, or restorative neural activity, such stimulation mayresult in collateral neural activity. In particular, neural stimulationdelivered beyond a certain intensity, level, or amplitude can give riseto seizure activity and/or other types of collateral activity, which maybe undesirable and/or inconvenient in a neural stimulation situation.

[0009] Seizure activity may originate at a seizure focus, which is acollection of neurons (e.g., on the order of 1000 neurons) exhibiting acharacteristic type of synchronous firing activity. In particular, eachneuron within a seizure focus exhibits a firing response known as aparoxysmal depolarizing shift (PDS). The PDS is a large magnitude, longduration depolarization that triggers a neuron to fire a train or burstof action potentials. Properly functioning feedback and/or feedforwardinhibitory signaling mechanisms cause an ensuing afterhyperpolarization,through which the neuron's membrane potential returns to ahyperpolarized state below its firing threshold. Following theafterhyperpolarization, the neuron may undergo another PDS.

[0010] The afterhyperpolarization limits the duration of the PDS,thereby helping to ensure that synchronous neural firing activityremains localized to the seizure focus. Inhibitory feedback signalingprovided by neurons surrounding a seizure focus, commonly referred to assurround inhibition, is particularly important in constraining seizureactivity to the seizure focus. In the event that inhibitory signalingmechanisms fail and/or are unable to overcome or counter PDS activity,neurons within the seizure focus recruit other neurons to which they aresynaptically coupled into their synchronous firing pattern. As a result,synchronous firing activity spreads beyond the seizure focus to otherareas of the brain. This can lead to a cascade effect in which seizureactivity becomes increasingly widespread and accompanying clinicalmanifestations become increasingly significant.

[0011] In view of the foregoing, it may be very important in any givenneural stimulation situation to determine an appropriate stimulationsignal amplitude, level, or intensity. However, an appropriatestimulation signal level may vary on a per-patient basis and possiblyover time for any particular patient. Notwithstanding, determination ofa neural stimulation threshold corresponding to a minimum ornear-minimum stimulation signal level that induces or generates ameasurable or monitorable patient response can provide a reference pointfor establishing a stimulation signal intensity appropriate for a neuralstimulation session.

[0012] Various types of neural stimulation thresholds exist. Forexample, an electromyography or electromyographic (EMG) threshold may bedefined as a lowest or near-lowest level of neural stimulation thatgenerates an EMG signal of a particular magnitude. An EMG signalprovides a measurement of electrical discharges associated with theinnervation of muscle fibers by one or more motor neurons, and the onsetof muscle fiber contraction in response to such electrical discharges.As another example, a sensation threshold may be defined as a lowest ornear-lowest level of neural stimulation at which a patient notices,perceives, or experiences a physical sensation such as a tingling orvibration in a muscle group or limb. As yet another example, a movementthreshold may be defined as a lowest or near-lowest level of neuralstimulation that induces a noticeable movement in a patient's limb.

[0013] Unfortunately, neural stimulation threshold testing can itselfinduce collateral neural activity. During a typical neural stimulationthreshold test procedure, a very low amplitude test stimulation signalis initially applied to a patient. The amplitude of the test stimulationsignal is then increased incrementally, while other test stimulationsignal parameters (e.g., frequency, pulse characteristics, duty cycle,etc . . . ) remain unchanged or unmodified. As its amplitude isincreased, the test stimulation signal is delivered to the patient in anuninterrupted or continuous manner. A lowest or near-lowest teststimulation signal amplitude that evokes a given type of patientresponse is correspondingly defined as the neural stimulation threshold.The patient is subsequently treated using a stimulation signal havingparameters identical to those of the test stimulation signal, with thepossible exception of stimulation signal amplitude, which may be apredetermined value based on the neural stimulation threshold.

[0014] Stimulation signal characteristics and manners in whichstimulation signals are applied to a target neural population cansignificantly affect the likelihood of inducing collateral neuralactivity. Conventional neural stimulation threshold test procedures failto adequately address this consideration, and thus may be susceptible toinducing seizure activity and/or other types of collateral neuralactivity. Hence, there is a need for systems and methods that reduce thelikelihood of inducing such activity during neural stimulation thresholdtesting.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015]FIG. 1 is a schematic illustration of a system for neuralstimulation threshold testing according to an embodiment of theinvention.

[0016]FIG. 2 is a graph illustrating several parameters that maydescribe or characterize a stimulation signal.

[0017]FIG. 3 is a flowchart illustrating various methods for neuralstimulation threshold testing according to an embodiment of theinvention.

[0018]FIG. 4 is a flowchart illustrating various methods for neuralstimulation threshold testing according to another embodiment of theinvention.

DETAILED DESCRIPTION

[0019] The following disclosure describes systems and methods forreducing the likelihood of inducing collateral neural activity duringthe application of test stimulation signals to a patient for the purposeof determining a threshold stimulation level that induces or evokes aparticular type of patient response, behavior, activity, sensation,perception, and/or reaction. In the context of the present invention,collateral neural activity may comprise seizure activity and/oressentially any other type of neural activity that may be undesirable,unwanted, unintended, and/or counterproductive relative to an intendedor desired neural activity associated with neural stimulation thresholdtesting.

[0020] Various methods in accordance with the present invention aredirected toward neural stimulation threshold test procedures thattemporally manage the application of test stimulation signals to apatient. Neural stimulation lasting beyond several seconds (e.g.,approximately 5 seconds) can lead to prolonged neural firing responsesknown as afterdischarges. Afterdischarges in a target neural populationincrease or tend to increase neural activity in the population, whichmay excite other neurons synaptically coupled to the target population.Afterdischarges can therefore increase the likelihood of inducingcollateral neural activity. Neural stimulation threshold test proceduresin accordance with the present invention may therefore apply limitedduration test stimulation signals to patients.

[0021] Neural stimulation applied to a target neural population canaffect the future excitability or firing likelihood of neurons in thetarget population. In particular, recently stimulated neurons mayexhibit enhanced excitability in the presence of subsequent stimulation.A neural population that receives sub-threshold stimulation during afirst time period may exhibit an increased firing susceptibility in thepresence of same stimulation applied during a second time period whenthe second time period and the first time period are separated by only abrief interval (e.g., seconds or several seconds). Moreover, neuralactivity, such as afterdischarges, may persist for many milliseconds orseconds after a stimulation signal is interrupted or terminated. Hence,neural stimulation threshold test procedures in accordance with thepresent invention may additionally or alternatively provide for aquiescent time interval between successive threshold determinationattempts during which test stimulation signals are not applied ordelivered to the target neural population.

[0022] Various methods in accordance with the present invention mayadditionally or alternatively be directed toward neural stimulationthreshold test procedures in which test stimulation signals and atreatment stimulation signal used to treat a patient may parametricallydiffer beyond their amplitudes. For example, depending upon stimulationsignal parameters, neurons within a target population may respond to astimulation signal in a synchronous manner. In particular, the abilityof neurons to synchronously respond to or follow a stimulation signal isa function of the stimulation signal's frequency. Neurons can readilyfollow a stimulation signal up to a frequency of approximately 100Hertz, but beyond this frequency their ability to follow the stimulationsignal degrades. Supra-threshold stimulation delivered to a targetneural population at a frequency that neurons can readily follow maydrive synchronous firing activity within the population. In view of theforegoing, a neural stimulation threshold test procedure in accordancewith the present invention may measure a first neural stimulationthreshold using one or more test stimulation signals having a firstfrequency; and subsequently calculate a second neural stimulationthreshold corresponding to a treatment stimulation signal that may havea second frequency different from the first frequency. The calculationof the second neural stimulation threshold may be performed inaccordance with one or more transformation equations, as described indetail below.

[0023]FIG. 1 is a schematic illustration of a system 100 for neuralstimulation threshold testing according to an embodiment of theinvention. In one embodiment, the system 100 comprises a stimulus unit120 configured to deliver stimulation signals to a patient 190 through apatient interface 109. The system 100 may further include a sensing unit180 coupled to the patient 190 and the stimulus unit 120.

[0024] The stimulus unit 120 is capable of generating and outputtingstimulation signals, which comprise electrical and/or magnetic signalsor stimuli. The stimulus unit 120 may perform, direct, and/or facilitateneural stimulation threshold test procedures in a manner that reducesthe likelihood of inducing collateral neural activity in accordance withthe present invention. Neural stimulation threshold test procedures mayinvolve the application of one or more test stimulation signals to apatient 190 in manners described in detail below. The stimulus unit 120may additionally perform, direct, and/or facilitate neural stimulationtreatment procedures to treat a particular neurological condition and/oraffect or influence a given type of neural activity. Neural stimulationtreatment procedures involve the application of a treatment stimulationsignal to a patient. The treatment stimulation signal, for example, istypically at a level or amplitude that corresponds to a result obtainedduring neural stimulation threshold test procedures (e.g., 20% to 80% ofa neural stimulation threshold).

[0025] The stimulus unit 120 may comprise a controller 130, a pulsesystem 140, and a set of controls/indicators 150. The controller 130 mayinclude a processor, a memory, and a programmable computer medium. Thecontroller 130 may be implemented as a computer or microcontroller,where the programmable medium comprises software loaded into the memory,and/or hardware that performs, directs, and/or facilitates neuralstimulation threshold test procedures in accordance with the methods ofthe present invention. The controls/indicators 150 can include a displaydevice, an input/output device, and/or other types of devices forexchanging commands and/or output with a computer.

[0026] The pulse system 140 can generate energy pulses, and send suchpulses to the patient interface 109. In one embodiment, the pulse system140 forms a portion of a Transcranial Magnetic Stimulation (TMS) devicethrough which externally applied magnetic stimulation signals createelectrical currents in the patient's brain. In such an embodiment, thepatient interface 109 may comprise an electromagnetic coil arrangementin a manner understood by those skilled in the art. In anotherembodiment, the pulse system 140 forms a portion of an electricalstimulation device; in this case the patient interface 109 may comprisean electrode array configured to deliver electrical stimulation signalsto the patient 190 as described in detail hereafter.

[0027] The patient interface 109 shown in FIG. 1 comprises an electrodearray 110 including a support member 112 and a plurality of electrodes114 carried by the support member 112. The electrode array 110 isgenerally implanted into the patient 190 and configured for corticalstimulation, deep brain stimulation, and/or other types of neuralstimulation. The electrode array 110 may comprise a corticalneural-stimulation device, such as a device described in U.S.application Ser. No. 09/802,808, incorporated herein by reference. Theelectrodes 114 may be coupled to the stimulus unit 120 by a link 116,which may be wire-based or wireless.

[0028] The electrode array 110 and the pulse system 140 can beintegrated into a single implantable stimulation apparatus, as describedin U.S. application Ser. No. 09/082,808. An integrated pulse system 140and electrode array 110 may be configured for implantation into apatient's skull such that the electrodes 114 can contact the patient'sdura matter or pia matter in a given cortical region. Such a device canhave an internal power source that can be implanted into the patient190, and/or an external power source coupled to the pulse system 140 viaelectromagnetic coupling or a direct connection. In alternateembodiments, the pulse system 140 is an external unit that is notimplanted into the patient 190. An external pulse system 140 can providestimuli to the electrodes 114 using RF energy, electromagnetism, or wireterminals exposed on the patient's scalp.

[0029] The sensing unit 180 may comprise a system or apparatus formeasuring or monitoring one or more types of patient reactions evoked orinduced in response to test stimulation signals applied during neuralstimulation threshold test procedures. The sensing unit 180 can becoupled to the stimulus unit 120 by at least one link 186, which may bewire-based and/or wireless. The stimulus unit 120 may issue a signalover the link 186 to synchronize the application of test stimulationsignals to the patient 190 with sensing unit measuring, monitoring,and/or recording operations. Depending upon embodiment details, thesensing unit 180 may also use the link 186 to communicate statusinformation and/or measurement results to the stimulus unit 120.

[0030] In one embodiment, the sensing unit 180 comprises an EMG devicecoupled to a plurality of electrodes or leads 182. The EMG device maydetect or monitor motor evoked potentials (MEPs) associated with musclefiber innervation in a manner understood by those skilled in the art. AnEMG threshold may be defined, for example, as a lowest or near-lowestlevel of neural stimulation that induces an MEP that departs frombaseline electrical activity by an amplitude greater than 50 microvoltspeak-to-peak under 1000×amplification and 20-1000 Hertz bandpassconditions. The electrodes 182 may comprise surface, percutaneous,and/or implanted probes, which may be positioned or configured tomeasure electrical activity associated with one or more muscles ormuscle groups. In one embodiment, the electrodes 182 include a groundlead and bipolar surface leads configured to monitor MEPs in aninterosseus muscle, a wrist extensor, a wrist flexor, and/or othermuscles.

[0031] Various embodiments of the present invention may alternatively oradditionally detect or determine other types neural stimulationthresholds, such as a sensation threshold, a movement threshold, anElectroencephalogram (EEG) threshold, a Magnetoencephalogram (MEG)threshold, and/or an imaging threshold. The structure and/or function ofthe sensing unit 180 may correspond to the type of neural stimulationthreshold under consideration. For example, to facilitate detection of amovement threshold, the sensing unit 180 may comprise a set of motiondetectors, accelerometers, and/or strain gauges configured to detect ormonitor one or more types of patient movements. To detect or determinean EEG threshold, the sensing unit 180 may comprise an EEG systemconfigured to monitor changes in a patient's EEG during neuralstimulation threshold test procedures. Such an EEG system may includeand/or utilize electrodes positioned upon the patient's scalp, and/orintracranially upon a brain surface or in a subcortical region.

[0032] To detect or determine an MEG threshold, the sensing unit 180 maycomprise an MEG system configured to monitor variations in the patient'sMEG in response to test stimulation signals. To measure or determine animaging threshold, the sensing unit 180 may comprise a neural imagingsystem configured to monitor and image a patient's neural activityduring neural stimulation threshold test procedures. Suitable neuralimaging systems include Magnetic Resonance Imaging (MRI) systems,functional MRI (fMRI) systems, or Positron Emission Tomography (PET)systems.

[0033] Different types of neural stimulation thresholds may vary withrespect to measurement or observation subjectivity, and/or sensitivityto stimulation signal intensity. In general, determination of an EMGthreshold may be a less subjective process than determination of amovement threshold, which may be a less subjective process thandetermination of a sensation threshold. Also, an EMG threshold may betriggered or induced at a lower stimulation signal intensity than asensation or a movement threshold. In general, a sensation threshold maybe triggered or induced at a lower stimulation signal intensity than amovement threshold, although this need not always be the case.Determination of movement and/or sensation thresholds may involve orrely upon human perception and verbal and/or visual feedback, and maynot require the use of a sensing unit 180.

[0034] As previously indicated, the stimulus unit 120 is configured todeliver stimulation signals to a patient 190; the stimulation signalsmay comprise test stimulation signals and/or treatment stimulationsignals. FIG. 2 is a graph illustrating several parameters that maydefine, describe, or characterize stimulation signals. A stimulus starttime to defines an initial point at which a stimulation signal isapplied to the patient interface 110. In one embodiment, the stimulationsignal may be a biphasic waveform comprising a series of biphasicpulses, and which may be defined, characterized, or described byparameters including a pulse width t₁ for a first pulse phase; a pulsewidth t₂ for a second pulse phase; and a pulse width t₃ for a singlebiphasic pulse. The parameters can also include a stimulus repetitionrate 1/t₄ corresponding to a pulse repetition frequency; a stimuluspulse duty cycle equal to t₃ divided by t₄; a stimulus burst time t₅that defines a number of pulses in a pulse train; and/or a pulse trainrepetition rate 1/t₆ that defines a stimulus burst frequency. Otherparameters include a peak current intensity I₁ for the first pulse phaseand a peak current intensity I₂ for the second pulse phase. Thoseskilled in the art will understand that pulse intensity or amplitude maydecay during one or both pulse phases, and a pulse may be acharge-balanced waveform. Those skilled in the art will furtherunderstand that in an alternate embodiment, pulses can be monophasic orpolyphasic.

[0035]FIG. 3 is a flowchart illustrating various methods for neuralstimulation threshold testing according to an embodiment of theinvention. In one embodiment, a method 300 may include a parameterdetermination procedure 302 involving determination, selection, orspecification of test stimulation signal parameters that may reduce alikelihood of inducing collateral neural activity. Depending uponembodiment details, one or more types of test stimulation signalparameter sets, selections, and/or settings may be preprogrammed intothe stimulus unit 120. A stimulus unit operator (e.g., a medicalprofessional) may select a particular set of test stimulation signalparameters using the stimulus unit's controls/indicators 150. Exemplarytest stimulation signal parameter selections that may reduce thelikelihood of inducing collateral neural activity are described indetail below with reference to FIG. 4.

[0036] The method 300 may additionally include a signal managementprocedure 304 that involves managing the temporal application of teststimulation signals to a patient 190 in a manner that reduces thelikelihood of inducing collateral neural activity. A stimulus unitoperator may use the stimulus unit's controls/indicators 150 to initiatethe signal management procedure 304. Particular manners of temporallymanaging test stimulation signal application in accordance with thepresent invention are described in detail below with reference to FIG.4. The method 300 may additionally include an observation or measurementprocedure 306 that involves observing and/or measuring one or moreneural stimulation thresholds based upon one or more patient reactionsand/or behaviors induced in response to the test stimulation signals.The observation procedure 306 may be performed using the sensing unit180 and/or human perception and feedback.

[0037] The method 300 may further include a calculation procedure 308involving calculation, mapping, and/or determination of a neuralstimulation threshold corresponding to a treatment stimulation signalthat is to be applied to the patient 190 for treating a neurologicalcondition and/or affecting neural activity. The treatment stimulationmay be parametrically distinct from one or more test stimulation signalswith respect to one or more parameters. Operations performed and/ordirected by the calculation procedure 308 may be based upon one or moremeasured and/or observed neural stimulation thresholds. The calculationprocedure 308 may involve the use of one or more conversion or mappingfunctions and/or data tables stored in a memory of the stimulation unit.Such functions and/or data tables may be based upon known relationshipsand/or one or more empirical measurement histories capable ofcorrelating test stimulation signal parameters with treatmentstimulation signal parameters for a range of neural stimulationthresholds as measured or observed in association with the observationprocedure 306.

[0038]FIG. 4 is a flowchart illustrating various methods for neuralstimulation threshold testing according to another embodiment of theinvention. In one embodiment, a method 400 includes a parameterdetermination procedure 402 that involves determining, specifying,and/or selecting test stimulation signal parameters that may reduce alikelihood of inducing collateral neural activity. In one embodiment,the pulse repetition frequency within a test stimulation signal may behigher than that within a treatment stimulation signal in order toreduce or minimize the likelihood that a significant number of neuronswithin a target neural population can synchronously respond to or followthe test stimulation signal. In general, a test stimulation signal needsto activate few or relatively few neurons within a target population toinvoke or elicit a measurable and/or observable patient response. Thus,the pulse repetition frequency of a test stimulation signal may behigher than a neural frequency that produces a significant degradationin behavior or function (e.g., above approximately 100 Hertz), withoutadversely affecting the likelihood that a sufficient number of neuronscan fire and evoke a patient response. In accordance with the presentinvention, exemplary test stimulation signal pulse repetitionfrequencies may be approximately 250 Hertz to approximately 400 Hertz,and in particular at the endpoints of this range.

[0039] An average amount of electrical current, charge, or energydelivered to a target neural population increases with increasing pulserepetition frequency, given constant or essentially constant teststimulation signal duration. As a result, a test stimulation signalhaving a higher pulse repetition frequency may be expected to elicit orevoke a measurable and/or observable patient response at a lower currentlevel than an equivalent duration test stimulation signal having a lowerpulse repetition frequency.

[0040] The method 400 may further include a signal application procedure404 that involves application or initiation of application of (a) afirst limited duration test stimulation signal having a low or very lowintensity or amplitude to a target neural population within the patient190; or (b) a next limited duration test stimulation signal having anincrementally or slightly higher intensity or amplitude than a previoustest stimulation signal to the target neural population. The use oflimited duration test stimulation signals may reduce or minimize thelikelihood of generating prolonged neural firing responses such asafterdischarges that can increase neural excitation outside of thetarget population to which the test stimulation signals are applied. Ingeneral, a limited duration test stimulation signal in accordance withthe present invention may be shorter than approximately 5 seconds.

[0041] The duration of a test stimulation signal applied in accordancewith the present invention may depend upon a type of neural stimulationthreshold currently under consideration. Thus, a limited duration teststimulation signal applied when determining one type of threshold may beshorter or longer than a limited duration test stimulation signalapplied when determining another type of threshold. In general, ashorter duration test stimulation signal may deliver a lower averageamount of electrical current, charge, or energy to the target neuralpopulation than a longer duration test stimulation signal givenequivalent or generally equivalent pulse repetition frequencies. Hence,a shorter duration test stimulation signal may require a higherelectrical current intensity, level, or amplitude to induce or evoke agiven type of patient response.

[0042] With respect to determination of a movement threshold, a shorterduration test stimulation signal may evoke or induce a sharper, betterdefined, and hence more easily observable patient movement than a longerduration test stimulation signal. With respect to sensation thresholddetermination, the duration of a test stimulation signal may need to besufficient to enable a patient 190 to accurately perceive and/or confirmperception of an induced sensation. Thus, in one embodiment, the signalapplication procedure 404 may apply test stimulation signals lasting atleast approximately 1 second or less when the method 400 involvesdetermination of a movement threshold; and/or apply test stimulationsignals lasting approximately 3 seconds when the method 400 involvesdetermination of a sensation threshold.

[0043] An EMG threshold may be determined in accordance with a varietyof EMG measurement and/or EMG signal analysis techniques. The signalapplication procedure 404 may apply test stimulation signals having aduration corresponding to an EMG measurement and/or EMG signal analysistechnique currently under consideration. In accordance with the signalapplication procedure 404, the stimulus unit 120 may issue asynchronization signal to the sensing unit 180 coincident or essentiallycoincident with the output of a test stimulation signal to initiate EMGsignal monitoring or recording operations in a manner understood bythose skilled in the art.

[0044] In one embodiment, the signal application procedure 404 may applytest stimulation signals to the patient 190 lasting approximatelyseveral milliseconds or on the order of tens of milliseconds when thesensing unit 180 is configured for EMG threshold measurement. Anexemplary test stimulation signal duration corresponding to EMGthreshold determination may be approximately 16 milliseconds. In such anembodiment, the signal application procedure 404 may repeat theapplication of a given test stimulation signal to the patient 190multiple times to increase an EMG signal to noise ratio (i.e., toaverage out noise); repeated applications of the test stimulation signalmay be separated by a minimum quiescent time interval as furtherdescribed below. The determination of an EMG threshold using teststimulation signals having a duration on the order of milliseconds ortens of milliseconds may performed in a manner analogous or generallyanalogous to conventional nerve conduction studies. In anotherembodiment, the signal application procedure 404 may apply teststimulation signals to the patient 190 lasting approximately 1 second to3 seconds.

[0045] In addition to the signal application procedure 404, the method400 may include a monitoring procedure 406 that involves monitoring orobserving the patient 190 and determining whether a patient behavior orreaction has been evoked or induced in response to the most recentlyapplied test stimulation signal. The monitoring procedure 406 mayinvolve the sensing unit 180 and/or human perception and feedback. Inthe event that the method 400 involves determination of an EMGthreshold, the monitoring procedure 406 may record and/or measure an EMGresponse during one or more portions of a test stimulation and/orthroughout its entirety. The monitoring procedure 406 may additionallyor alternatively perform EMG signal analysis operations to enhance MEPdetectability. Such EMG signal analysis operations may includedetermination of changes in MEP firing or activation rates,determination of changes in MEP activation complex durations or temporalwidths, root-mean-square (RMS) amplitude analysis, power spectrumanalysis, correlation analysis, and/or one or more other statisticalanalyses.

[0046] The method 400 may also include an adjustment procedure 408involving modification or adjustment of test stimulation signalintensity or amplitude if no patient response was evoked in associationwith the signal application procedure 404. In the absence of an evokedresponse, test stimulation signal intensity may be increased inaccordance with a particular increment, for example, by 0.5 or 1.0milliamps, or by a given percentage. The method 400 may additionallyinclude a waiting procedure 410 involving waiting or pausing for aminimum quiescent time interval following application of a most recenttest stimulation signal to the patient 190. After the minimum quiescenttime interval has elapsed, the method 400 may return to the signalapplication procedure 404.

[0047] The use of a minimum quiescent time interval after theapplication of a given limited duration test stimulation signal mayreduce or minimize the likelihood that neurons within the target neuralpopulation will have an increased firing susceptibility or re-excitationlikelihood during application of a subsequent test stimulation signal. Aminimum quiescent time interval may range from several seconds toseveral minutes. In an exemplary embodiment, the minimum quiescent timeinterval is approximately 1 minute. In an alternate embodiment, theminimum quiescent time interval may be shortened or increased dependingupon a cumulative number of test stimulation signals that had beenapplied to the patient 190.

[0048] The method 400 may additionally include a threshold measurementprocedure 420 involving measurement or determination of a neuralstimulation threshold corresponding to the most recently applied teststimulation signal that evoked or induced a patient reaction orresponse. In one embodiment, the neural stimulation thresholdcorresponding to a given test stimulation signal is the electricalcurrent level, intensity, or amplitude at which the test stimulationsignal evoked or induced a particular type of patient response.

[0049] The method 400 may further include a threshold calculationprocedure 422 involving calculation of a neural stimulation thresholdcorresponding to a treatment stimulation signal to be applied to thepatient. In calculating a neural stimulation threshold corresponding toa treatment stimulation signal, the threshold calculation procedure 422may use one or more transformation formulas and/or conversionrelationships, which may be programmably stored within the stimulus unit120. Such transformation formulas and/or conversion relationships may bebased upon known parameter relationships and/or empirical data measuredacross a variety of test stimulation signal parameter configurations,and they may be generated using curve fitting and/or numerical modelingprocedures. In one embodiment, a transformation formula appropriate fortest stimulation signals and treatment stimulation signals approximately3 seconds or longer in duration may be of the following general form:

I ₂(f ₂)=I ₁(f ₁)*(1+k*(f ₁ **q))/((1+k*(f ₂ **q))  [1]

[0050] In the above equation, I₂ may be a peak, average, or RMS currentlevel that defines or establishes a calculated neural stimulationthreshold corresponding to the treatment stimulation signal; f₂ is apulse repetition frequency associated with the treatment stimulationsignal; I₁ is a measured neural stimulation threshold corresponding to atest stimulation signal; f₁ is a pulse repetition frequencycorresponding to this test stimulation signal; and k and q areconstants. The values of k and q may depend upon the nature of the teststimulation signals and/or the treatment stimulation signal. In anexemplary embodiment, for anodic monopolar test stimulation signals, kand q may respectively equal −0.9637 and 0.0249. For bipolar teststimulation signals, k and q may respectively equal −1.0047 and 0.0032.

[0051] The above conversion formula may scale linearly, quasi-linearly,or nonlinearly for test stimulation signal durations shorter than 3seconds; the manner of scaling may depend upon how closely a teststimulation signal's duration approaches 3 seconds. In general, thoseskilled in the art will understand that additional and/or other types oftransformation formulas may be defined, derived, and/or determined inaccordance with particular test and/or treatment stimulation signalparameter characteristics under consideration.

[0052] A calculated neural stimulation threshold may be larger orsmaller than the measured or observed neural stimulation threshold,depending upon test stimulation signal parameters and treatmentstimulation signal parameters. The treatment signal may beparametrically distinct from the test stimulation signals; inparticular, the treatment stimulation signal may have a different (e.g.,lower) pulse repetition frequency and/or a longer (possibly continuous)duration than the test stimulation signals. The treatment stimulationsignal may be delivered to the target neural population at an intensity,level, or amplitude that is a particular function or fraction of thecalculated neural stimulation threshold.

[0053] Various methods for neural stimulation threshold testing inaccordance with the present invention may employ additional, fewer,and/or other procedures than those described above. For example, teststimulation signals may differ from a treatment stimulation signal withrespect to additional or other parameters than those described above. Asanother example, a procedure may include a step of verifying acalculated neural stimulation threshold by applying a treatmentstimulation signal to the patient 190 at the calculated threshold, anddetermining whether a patient reaction occurs that is equivalent orgenerally equivalent to that which occurred during test stimulationsignal application. A procedure may also record and store eventinformation, data, and/or measurements obtained during test stimulationsignal application. The disclosure herein provides for these and othervariations, and is limited only by the following claims.

I/we claim:
 1. A method of determining a neural stimulation thresholdfor a patient comprising the steps of: applying a test stimulationsignal to the patient; monitoring the patient for a response to the teststimulation signal; determining a first neural stimulation thresholdcorresponding to a lowest intensity test stimulation signal that evokesa patient response; and calculating a second neural stimulationthreshold based upon the first neural stimulation threshold, the secondneural stimulation threshold corresponding to a treatment stimulationsignal directed toward affecting a neural activity within the patient.2. The method of claim 1, wherein the calculating step is performedusing a transformation equation.
 3. The method of claim 1, wherein thetreatment stimulation signal differs from the test stimulation signalwith respect to a plurality of parameters.
 4. The method of claim 1,wherein the treatment stimulation signal has a different pulserepetition frequency than the test stimulation signal.
 5. A method ofdetermining a neural stimulation threshold for a patient comprising thesteps of: applying a plurality of limited duration test stimulationsignals to the patient; monitoring the patient for a response to a teststimulation signal; and determining a first neural stimulation thresholdcorresponding to a lowest intensity test stimulation signal that evokesa patient response.
 6. The method of claim 5, wherein at least one teststimulation signal has a duration between approximately 10 millisecondsand approximately 5 seconds.
 7. The method of claim 5, wherein at leastone test stimulation signal has a duration of less than approximately 5seconds.
 8. The method of claim 5, wherein at least one test stimulationsignal has a duration between approximately 2 seconds and approximately3 seconds.
 9. The method of claim 5, wherein at least one teststimulation signal has a duration of approximately 1 second.
 10. Themethod of claim 5, wherein each test stimulation signal has a durationbetween approximately 10 milliseconds and approximately 5 seconds. 11.The method of claim 5, wherein each test stimulation signal has aduration of less than approximately 5 seconds.
 12. The method of claim5, wherein each test stimulation signal has a duration betweenapproximately 2 seconds and approximately 3 seconds.
 13. The method ofclaim 5, wherein each test stimulation signal has a duration ofapproximately 1 second.
 14. The method of claim 5, wherein at least onetest stimulation signal has a duration that is dependent upon acumulative number of test stimulation signals that have been applied tothe patient.
 15. The method of claim 5, wherein at least one teststimulation signal has a duration that corresponds to a type of patientresponse under consideration.
 16. The method of claim 5, wherein atleast two test stimulation signals are temporally separated by a minimumtime interval.
 17. The method of claim 5, wherein at least two teststimulation signals are temporally separated by a minimum time intervalranging between approximately 10 seconds and 4 minutes.
 18. The methodof claim 5, wherein at least two test stimulation signals are temporallyseparated by a minimum time interval of approximately 1 minute.
 19. Themethod of claim 5, wherein each test stimulation signal is temporallyseparated by a minimum time interval.
 20. The method of claim 5, furthercomprising the step of calculating a second neural stimulation thresholdbased upon the first neural stimulation threshold, the second neuralstimulation threshold corresponding to a treatment stimulation signaldirected toward affecting neural activity within the patient.
 21. Amethod of determining a neural stimulation threshold for a patientcomprising the steps of: applying a plurality of test stimulationsignals to the patient; monitoring the patient for a response to a teststimulation signal; and determining a first neural stimulation thresholdcorresponding to a lowest intensity test stimulation signal that evokesa patient response, wherein successive test stimulation signals appliedto the patient are temporally separated by a minimum time interval. 22.The method of claim 21, wherein the minimum time interval is greaterthan approximately 10 seconds.
 23. The method of claim 21, wherein theminimum time interval is less than approximately 4 minutes.
 24. Themethod of claim 21, wherein the minimum time interval is greater thanapproximately 10 seconds and less than approximately 4 minutes.
 25. Themethod of claim 21, wherein the minimum time interval is approximately 1minute.
 26. The method of claim 21, wherein the test stimulation signalscomprise electrical stimulation signals.
 27. The method of claim 21,wherein at least one test stimulation signal has a duration betweenapproximately 10 milliseconds and approximately 5 seconds.
 28. Themethod of claim 21, wherein each test stimulation signal has a durationbetween approximately 10 milliseconds and approximately 5 seconds. 29.The method of claim 21, further comprising the step of calculating asecond neural stimulation threshold based upon the first neuralstimulation threshold, the second neural stimulation thresholdcorresponding to a treatment stimulation signal directed towardaffecting neural activity within the patient.
 30. A method ofdetermining a neural stimulation threshold for a patient comprising thesteps of: selecting a set of test stimulation signal parameters thatreduce a likelihood of inducing seizure activity in the patient;applying a plurality of test stimulation signals to the patient;monitoring the patient for a response to a test stimulation signal;determining a first neural stimulation threshold corresponding to alowest intensity test stimulation signal that evokes a patient response;and calculating a second neural stimulation threshold based upon thefirst neural stimulation threshold, the second neural stimulationthreshold corresponding to a treatment stimulation signal directedtoward affecting neural activity within the patient, wherein thetreatment stimulation signal differs from at least one test stimulationsignal with respect to a plurality of parameters.
 31. The method ofclaim 23, wherein the treatment stimulation signal has a different pulserepetition frequency than at least one test stimulation signal.
 32. Aneuro-stimulation system comprising: a stimulus unit configured todeliver a set of test stimulation signals to a patient; and a controlleroperatively coupled to the stimulus unit, the controller including acomputer operable medium containing instructions that define a set ofparameters corresponding to each test stimulation signal and at leastone from the group of a maximum duration corresponding to each teststimulation signal and a minimum time interval between at least two teststimulation signals.
 33. The neuro-stimulation system of claim 32,wherein the duration corresponding to each test stimulation signal isbetween approximately 10 milliseconds and approximately 5 seconds. 34.The neuro-stimulation system of claim 32, wherein the durationcorresponding to each test stimulation signal is less than approximately5 seconds.
 35. The neuro-stimulation system of claim 32, wherein theduration corresponding to each test stimulation signal is betweenapproximately 2 seconds and approximately 3 seconds.
 36. Theneuro-stimulation system of claim 32, wherein the minimum time intervalis greater than approximately 10 seconds.
 37. The neuro-stimulationsystem of claim 32, wherein the minimum time interval is less thanapproximately 4 minutes.
 38. The neuro-stimulation system of claim 32,wherein the minimum time interval is greater than approximately 10seconds and less than approximately 4 minutes.
 39. The neuro-stimulationsystem of claim 32, wherein the minimum time interval is approximately 1minute.
 40. The neuro-stimulation system of claim 32, wherein thestimulus unit is additionally configured to deliver a set of treatmentstimulation signals to the patient, at least one treatment stimulationsignal directed toward affecting a neural activity within the patient.41. The neuro-stimulation system of claim 40, wherein the treatmentstimulation signal has a different frequency than a test stimulationsignal.
 42. The neuro-stimulation system of claim 32, wherein thestimulus unit comprises: an electrode array configured for implantationinto the patient; and a pulse system coupled to deliver the set of teststimulation signals to the electrode array.
 43. The neuro-stimulationsystem of claim 32, further comprising a sensing unit configured todetect a patient response to a test stimulation signal.
 44. Theneuro-stimulation system of claim 32, wherein the sensing unit comprisesat least one form the group of an EMG device, an EEG device, an MEGdevice, a neural imaging device, and a motion detection device.
 45. Theneuro-stimulation system of claim 32, wherein the computer operablemedium contains program instructions for causing the controller toperform the steps of: applying a test stimulation signal to the patient;and using a first neural stimulation threshold corresponding to a lowestintensity test stimulation signal that evokes a patient response todetermine a second neural stimulation threshold, the second neuralstimulation threshold corresponding to a treatment stimulation signaldirected toward affecting a neural activity within the patient.
 46. Thesystem of claim 45, wherein the treatment stimulation signal differsfrom the test stimulation signal with respect to a plurality ofparameters.
 47. The system of claim 45, wherein the treatmentstimulation signal has a different pulse repetition frequency than thetest stimulation signal.
 48. The system of claim 32, wherein thecomputer operable medium contains program instructions for causing thecontroller to perform the step of applying a plurality of limitedduration test stimulation signals to the patient, wherein at least onetest stimulation signal has a duration of less than approximately 5seconds.
 49. The system of claim 48, wherein each test stimulationsignal has a duration of less than approximately 5 seconds.
 50. Thesystem of claim 48, wherein the computer operable medium containsprogram instructions for causing the controller to separate successivetest stimulation signals by a minimum time interval.
 51. The system ofclaim 50, wherein the minimum time interval is greater thanapproximately 10 seconds.
 52. The system of claim 50, wherein theminimum time interval is less than approximately 4 minutes.
 53. Thesystem of claim 52, wherein the minimum time interval equalsapproximately 1 minute.